Hyaluronan or hyaluronic acid is a linear mucopolysaccharide constituted by N-acetyl-D-glucosamine and D-glucuronic acid repeating units. Hyaluronic acid was first found in the vitreous body of a cattle eye by Meyer and Palmer in 1934, and then was found in other tissues such as extracellular matrix (ECM) and synovial fluid of the joints. Hyaluronic acid is a viscoelastic fluid filled in the space between cells and collagenous fibers and coated on some epidermal tissues. Hyaluronic acid plays an important role in the biological organism, firstly as a mechanical support of the cells of many tissues, such as the skin, the tendons, the muscles and cartilage. Hyaluronic acid also performs other functions in the biological processes, such as moistening of tissues, lubrication, and cellular migration.
Hyaluronic acid may be extracted from natural tissues, such as a rooster's comb, or also from certain bacteria. The molecular weight of hyaluronic acid obtained by extraction varies due to the source and the extraction process and is generally in the range of several millions to several tens of millions Dalton.
Hyaluronic acid, its molecular fractions and its salts have been used in pharmaceutical, surgical and cosmetic fields and in the field of biodegradable polymer materials. However, since hyaluronic acid is very expensive and is biodegraded quite easily, its application is limited. In past years, many methods have been developed to modify hyaluronic acid in order to increase its resistance to biodegradation.
In U.S. Pat. No. 5,462,976, tertiary amine salt of a glycosaminoglycan (such as hyaluronic acid) is reacted with a photoreactive compound to undergo esterification. The ester product is then exposed to UV radiation to form a crosslinked water-insoluble glycosaminoglycan derivative.
Francesco della Valle et al. at Fidia, S.p.A. in U.S. Pat. No. 4,851,521 discloses a process for preparing esters of hyaluronic acid. Hyaluronic acid is converted into an ammonium salt that can be dissolved in an organic solvent, and is then reacted with an aliphatic type alcohol to form an ester bond on hyaluronic acid. An ester linkage is formed by the reaction of the carboxyl group (COOH) on hyaluronic acid and the hydroxy group on the alcohol.
Francesco della Valle et al. in U.S. Pat. No. 4,957,744 discloses a process for preparing cross-linked esters on hyaluronic acid. Hyaluronic acid is first converted into an ammonium salt. Then, a polyhydric alcohol is used to react with more than two carboxyl groups (COOH) on hyaluronic acid, thus forming a cross-linked esterified hyaluronic acid.
Francesco della Valle et al. in U.S. Pat. No. 5,122,598 discloses a process for preparing polysaccharide esters. Polysaccharide, such as carboxymethylcellulose and carboxymethylchitin, is first converted into an ammonium salt. Then, an alcohol is used to react with the carboxyl group (COOH) on hyaluronic acid, thus forming a polysaccharide ester.
Francesco della Valle et al. in U.S. Pat. No. 5,202,431 discloses a process for preparing partial esters of hyaluronic acid. Hyaluronic acid is first converted into an ammonium salt. Then, an aliphatic alcohol is used to react with the carboxyl group (COOH) on hyaluronic acid. Then, the hyaluronic acid ester is salified with a therapeutically active amine.
Francesco della Valle et al. in U.S. Pat. No. 5,336,767 discloses a process for preparing total or partial esters of hyaluronic acid. Hyaluronic acid is first converted into an ammonium salt. Then, a pharmacologically active alcohol, such as cortisone, hydrocortisone or prednisone is reacted with the carboxyl group (COOH) on hyaluronic acid via an ester linkage.
Francesco della Valle et al. in U.S. Pat. No. 5,442,053 discloses a composition including hyaluronic acid and a pharmacologically active substance. A hyaluronic acid fraction with a molecular weight between 50,000 and 100,000 is particularly suitable for wound healing and hyaluronic acid with a molecular weight between 500,000 and 730,000 is particularly suitable for intraarticular injection.
Zefferino Righetto et al. in U.S. Pat. No. 5,856,299 discloses highly reactive esters of carboxy polysaccharide and carboxy polysaccharides derived therefrom. Hyaluronic acid is first converted into a salt of hyaluronic acid capable of being dissolved in an organic solvent. Then, an aromatic alcohol is used to react with the carboxyl group (COOH) on hyaluronic acid, thus forming a highly reactive esterified hyaluronic acid suitable for biomedical and pharmaceutical fields.
However, there is still a need to modify hyaluronic acid in order to improve its properties or various applications.